Ethacrynic acid-like compounds and use thereof to treat glaucoma

ABSTRACT

Compounds structurally related to ethacrynic acid are described. The compounds are useful for controlling intraocular pressure. Unlike ethacrynic acid, the compounds of the present invention are capable of effectively penetrating the cornea. Methods of controlling intraocular pressure via topical application of one or more of the compounds to the eye and topical ophthalmic compositions useful in the treatment of glaucoma are also described.

BACKGROUND OF INVENTION

The present invention relates to certain new compounds believed to beuseful in the treatment of glaucoma. The compounds are structurallyrelated to ethacrynic acid, which is a compound having diuretic andanti-allergic properties and which has been described as being useful inthe treatment of glaucoma.

Glaucoma is a progressive disease which leads to optic nerve damage,and, ultimately, partial or total loss of vision. The causes of thisdisease have been the subject of extensive studies for many years, butare still not fully understood. The principal symptom of the disease isan elevated pressure within the eye caused by excess intraocular fluid(i.e., "aqueous humor").

The reasons why the excess fluid accumulates are not fully understood.It is known that the elevated intraocular pressure ("IOP") can be atleast partially controlled by administering drugs which affect eitherthe production of aqueous humor within the eye or the flow of aqueoushumor out of the eye. The glaucoma therapies currently availableprimarily involve the use of drugs which act to reduce production ofaqueous humor by the ciliary body of the eye. These therapies have beengenerally effective in the majority of patients. However, it is notalways possible to control chronic elevations of IOP by reducing theamount of aqueous humor production, particularly in cases whereobstructed outflow of aqueous humor is contributing to the excess ofaqueous humor and consequent elevation of IOP. Moreover, the reductionof aqueous humor production creates a risk that the avascular tissues ofthe eye, particularly the lens and the cornea, will be damaged due to aninadequate supply of nutrients and/or hydration caused by the reducedproduction of aqueous humor. The possible use of agents which increasethe outflow of aqueous humor to control IOP has therefore been a topicof great interest to scientists engaged in glaucoma research.

The use of ethacrynic acid ("ECA") to increase the outflow of aqueoushumor has been reported in the literature. This use is described in U.S.Pat No. 4,757,089 issued to David L. Epstein. The Epstein '089 patentdescribes a method of increasing aqueous humor outflow by topicallyadministering ECA, or analogs of ECA which are capable of reacting withsulfhydryl groups in the trabecular meshwork of the eye. Epsteinpostulates that chemical modification of cellular sulfhydryl groups byECA or ECA analogs alters the egress of aqueous humor from thetrabecular meshwork.

Unfortunately, there are serious limitations on the topical ophthalmicuse of ECA due to its poor penetration of the cornea. ECA, a carboxylicacid with a pK of 3.5, exists essentially exclusively (greater than99.9%) in its ionic form, the carboxylate anion, at physiological pH(7.4). Therefore, in spite of the favorable lipophilicity of the neutralspecies (calculated log P of 3.19), the species present at physiologicpH, the ionic form, has an extremely unfavorable lipophilicity(experimental log P is -1.15); therefore, the ability of ECA or analogsto penetrate lipophilic corneal membranes at physiological pH isextremely poor. The limited ocular penetration of these acidic compoundsseverely limits the practical value of ECA in glaucoma therapy, becauseif the drug can not effectively penetrate the cornea, a therapeuticlevel of the drug at the postulated site of action (i.e., the trabecularmeshwork) will not be achieved.

SUMMARY OF THE INVENTION

The present invention is directed to the provision of certain newcompounds considered to be beneficial in the treatment of glaucoma. Thecompounds are also believed to have anti-allergic properties. Thecompounds incorporate an amine functionality which has an unusually lowpK value, and are capable of penetrating the cornea fairly rapidly,unlike ethacrynic acid. The invention also entails methods ofcontrolling IOP by topically applying one or more of the subjectcompounds and related compounds to the affected eyes, and associatedtopical ophthalmic compositions.

DESCRIPTION OF PREFERRED EMBODIMENTS

The compounds utilized in the present invention have the followingstructure: ##STR1## wherein: X is O, S or SO_(m), wherein m is 1 or 2:

n is O, 1 or 2;

W and Y are independently selected from hydrogen, halogen (F, Cl Br),alkyl(C₁₋₄), alkoxy(C₁₋₄), or alkyl(C₁₋₃) substituted by one or morefluorine atoms;

R₁ is alkyl (C₁₋₄), straight chain or branched, and may be substitutedwith one or more of alkoxy (C₁₋₄), alkoxycarbonyl(C₁₋₅), halogen (F, Cl,Br), or NR₃ R₄ ;

R₂ is hydrogen, lower alkyl (C₁₋₄), hydroxymethyl, alkoxy(C₁₋₄)methyl,alkoxy(C₁₋₄)alkoxy(C₂₋₄)methyl, or hydroxyalkoxy(C₂₋₄)methyl;

G is NR₃ R₄, alkyl(C₁₋₄) or hydrogen, or G and R₂ together with theintervening carbon atom may be incorporated into a saturatedheterocyclic ring of the following structure: ##STR2## wherein Q, L₁,and R₅ are as defined below; R₃ and R₄ are independently selected fromhydrogen, alkyl (C₁₋₆), alkenyl (C₃₋₈), or alkynyl (C₃₋₈), straightchain or branched, and may be substituted with one or more of halogen(F, Cl, Br), hydroxyl, alkoxy(C₁₋₄), alkyl (C₁₋₄)sulfone, oralkoxycarbonyl (C₁₋₅), provided that R₃ and R₄ cannot both be hydrogen;or R₃ and R₄ together with the nitrogen atom of the NR₃ R₄ group may beincorporated into a saturated heterocyclic ring selected from: ##STR3##p is 1-4; L₁ and L₂ are independently chosen from --(CH₂ )q--, wherein qis 2 or 3, or --CHR₇ CH₂ --;

Q is O, NR₆, S or SO₂ ;

R₅ is hydrogen, alkyl (C₁₋₄), alkoxy (C₁₋₃), alkoxy(C₁₋₃)alkyl(C₂₋₄),alkoxycarbonyl (C₁₋₅) or hydroxyalkyl (C₁₋₃);

R₆ is hydrogen, hydroxyalkyl (C₂₋₄), alkoxy(C₁₋₃)alkyl(C₂₋₄), alkyl(C₂₋₄)carbonyl or alkyl (C₁₋₃)sulfonyl; and

R₇ is alkyl (C₁₋₄), alkoxy (C₁₋₃), alkoxycarbonyl(C₁₋₅) or hydroxyalkyl(C₁₋₃), provided that at least one but not both of R₁ and G include anamine functionality.

The invention also encompasses pharmaceutically acceptable salts of theabove-identified compounds. The compounds may exist in isomeric form, sothe use of pure isomers of the compounds is contemplated, as well as theuse of racemic mixtures of the isomers.

Certain compounds of formula (I), wherein X is O, are known. See, forexample, U.S. Pat. Nos. 4,342,782 and 4,390,537; the entire contents ofthe foregoing patents are hereby incorporated in the presentspecification by reference.

The compounds of the present invention can be prepared by one skilled inthe art of organic chemistry by the general synthetic proceduresdescribed in U.S. Pat. No. 4,342,782 or modifications thereof, such asthe procedures illustrated in Equations 1 and 2 below, wherein R₁, W, Y,R₂, and G are as described above, and X is halogen (chloride, bromide oriodide): ##STR4## That is, the desired phenolic ketones 1 can bealkylated with an appropriately substituted alkyl halide 2 using asuitable base, such NaH, KOH, DBU or the like, in a compatible inertsolvent to provide the intermediate ethers 3. These intermediate etherscan be converted into the desired α-methylene ketones 4 by initialreaction with formaldehyde and a secondary amine, such as dimethylamine,to give the so-called Mannich salt, which can be readily dehydroaminatedupon treatment with weak base, such as sodium carbonate.

Compounds of formula (I) wherein X is SO₂ can be prepared as illustratedin Equation 3 below: ##STR5## The desired intermediates 5 can beprepared from the requisite aniline by procedures described inNetherlands Patent Application 6,506,045 or modifications thereof.Incorporation of the desired amino group to provide compounds 6 can beaccomplished by procedures known in the art, but preferably bydisplacement of an aryl or alkyl sulfonate ester under mildly basicconditions, or by using conditions of the Mitsunobu reaction, diethylazodicarboxylate-triphenylphosphine.

Preferred compounds of formula (I) are those wherein G is NR₃ R₄.Particularly preferred are the following compounds: ##STR6##

In order to be therapeutically effective, agents applied topically tothe eye must be able to traverse the external surfaces of the eye,principally the cornea but also of interest are the sclera andconjunctiva, in order to reach their target tissues. As pointed out byDaveson (Physiology of the Eye, 5th ed., p. 118, Pergamon, 1990),lipid-soluble substances are expected to, and indeed have been shown to,readily pass into the membranes of the cornea because they easily passinto the lipid membranes of the cells while lipid insoluble substancespenetrate the cornea with difficulty. Therefore, for a substance whichis an organic acid, the degree of dissociation is an importantconsideration; similarly, for a substance which is an organic base, thedegree of formation of the conjugate acid is an equally importantconsideration, since for either type of substance the penetration of thecornea by the more lipophilic unionized species is more rapid than thatof the ion. The major role of lipophilicity in affecting drugpenetration of the cornea and conjunctiva has been demonstrated for avariety of classes of therapeutic agents when applied topically to theeye. See, for example, W. Wang, et al, Current Eye Research, 10, 571(1991) and references cited therein.

A measure of the ability of a substance to associate with lipidenvironments can be ascertained from the extent of its partitioningbetween two immiscible liquid phases. This value, the partitioncoefficient or distribution coefficient, can be determinedexperimentally using, for example, water and n-octanol as the liquidphases; there is considerable literature available concerning thesemethods; see, for example, W. J. Dunn, III, J. Block and R. S. Pearlman,eds., Partition Coefficient: Determination and Estimation, PergamonPress, 1986, and M. S. Mirrlees, et al., J. Med. Chem, 19, 615 (1976).However, because of the time consuming nature of these experimentaldeterminations and as a means to estimate the partitioningcharacteristics of compounds which are either not available or have notyet been prepared, empirical procedures have been developed forcalculating partition coefficients. One such approach which has receivedwide acceptance is the CLOGP algorithm developed by the Pomona CollegeMedicinal Chemistry Project. For a discussion of this application, seeLeo in "Comprehensive Medicinal Chemistry", Vol. 4, p. 295. Thisprocedure has been used for estimating the partition coefficients forrepresentative compounds of formula (I).

A basic premise of the present invention is that compounds of formula(I) do not contain a carboxylic acid functionality as a structuralelement, but do have incorporated into their structure an aminefunctionality which has an unusually low pK value, e.g., 5.4-7.4, eitherwithin group G or R₁, in formula (I), but not both. The acid salt formsof these compounds will be highly soluble under mildly acidicconditions, conditions which are desirable for enhanced stability of thecrucial ∝-methylene-ketone moiety of these compounds, and furthermorethese conditions are acceptable for ocular formulations. Atphysiological pH, however, the compounds of this invention will existprimarily in the free base form (non-charged species); this neutralspecies will have a reduced solubility compared to the charged species,but will be significantly more lipophilic than the charged species, aproperty which will facilitate rapid transport through the lipophiliccorneal membranes, thus allowing the compounds to gain access to thetarget tissue, the trabecular meshwork. That is, the cationic form ofthe compounds of this invention which would be present in mildly acidicformulations will upon topical administration to the eye be transformedto the neutral free base form under the physiological conditions of thetear film. The lipophilic neutral compounds will cross the cornea morereadily than the anionic form of ethacrynic acid present atphysiological pH. The physiochemical properties of the compounds of thepresent invention are further illustrated by the data presented in thefollowing table:

    ______________________________________                                                                        Estimated                                             Calculated              Neutral                                               Log P                   Species at                                    Compound                                                                              CLOGP       Calculated pK                                                                             pH 7.4 (%)                                    ______________________________________                                         3      3.51        6.3         92.6                                           6      3.08        6.1         95.2                                           9      2.60        5.5         98.7                                          10      2.90        6.0         96.2                                          11      3.01        6.4         90.9                                          12      2.71        6.2         94.1                                          13      2.60        5.5         98.7                                          14      2.42        5.5         98.7                                          ______________________________________                                    

Another premise of the present invention is that a compound whichmaintains an acceptable level of reactivity toward physiologicallyrelevant nucleophiles (most probably specific protein mercapto groups)while displaying an acceptable level of solubility will betherapeutically useful in the treatment of ocular hypertension. It isfurther maintained that the carboxylic acid group present in ethacrynicacid is not a requirement for eliciting the desired response, and thatthis group can be replaced as indicated above.

Due to their improved aqueous solubility at acceptable formulation pHvalues (i.e., 4.7 to 6.0) and their acceptable lipophilicity atphysiological pH, the compounds of formula (I) will readily gain accessto the target tissue, the trabecular meshwork cells, following topicaladministration to the eye. The exact dosage regimen may be determined byclinicians. In general, an ophthalmic composition containing one or moreof the compounds of formula (I) will be applied to the eye one to fourtimes per day, perferably one to two times per day. The dosage will bean amount effective to achieve the therapeutic objectives of loweringelevated intraocular pressure or controlling intraocular pressure so asto prevent such elevations. Such an amount will be referred to herein as"a therapeutically effective amount".

The compounds of formula (I) may be incorporated in various types ofophthalmic compositions, in accordance with formulation techniques knownto those skilled in the art. As these compounds are relatively solublein water, aqueous formulations, particularly solutions, are preferred.The compounds will be contained in such compositions in an amounteffective to control elevations of intraocular pressure; such amountwill generally be in the range of from about 0.01 to about 5 percent byweight, based on the total weight of the composition ("wt. %"), andpreferably from about 0.1 to about 1 wt. %.

The compositions may contain one or more chemical preservatives toprevent microbial contamination of the compositions when dispensed inmultiple dose containers. Preservatives which may be employed includebenzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, and otheragents known to those skilled in the art. Such preservatives aretypically employed at a level of from about 0.001 to 1.0 wt. %. Thecompositions may also contain one or more buffering agents to maintainthe pH of the compositions at or near the physiological pH of 7.4.Examples of buffering agents which may be utilized include phosphates,borates, citrates and carbonates. The tonicity of the compositions willpreferably be at or near the tonicity of human tears (i.e.,approximately 300-320 milliosmoles). The tonicity of the compositionscan be adjusted, as needed, by adding sodium chloride, mannitol or otherconventional and well-known agents. It may also be desirable to adjustthe viscosity of the compositions, so as to improve the comfort of thecompositions when topically applied to the eye. Viscosity-buildingagents which may be utilized include polyvinyl alcohol, tyloxapol,methylcellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone,carboxyvinyl polymers, and various other agents known to those skilledin the art.

What is claimed is:
 1. A method of controlling intraocular pressurewhich comprises topically applying to the affected eye a therapeuticallyeffective amount of an ophthalmic composition comprising an amount of acompound of the following formula effective to control intraocularpressure: ##STR7## wherein: X is O, S, or SO_(m), and m is 1 or 2;n isO, 1 or 2; W and Y are independently selected from hydrogen, halogen,alkyl(C₁₋₄), alkoxy(C₁₋₄), or alkyl(C₁₋₃) substituted by one or morefluorine atoms; R₁ is alkyl(C₁₋₄), straight chain or branched, and maybe substituted with one or more of alkoxy(C₁₋₄), alkoxycarbonyl(C₁₋₅),halogen or NR₃ R₄ ; R₂ is hydrogen, lower alkyl (C₁₋₄), hydroxymethyl,alkoxy(C14)methyl, alkoxy(C₁₋₄) alkoxy(C₂₋₄)methyl, orhydroxyalkoxy(C₂₋₄)methyl; G is NR₃ R₄, alkyl(C₁₋₄) or hydrogen, or Gand R₂ together with the intervening carbon atom may be incorporatedinto a saturated heterocyclic ring of the following structure: ##STR8##R₃ and R₄ are independently selected from hydrogen, alkyl (C₁₋₆),alkenyl (C₃₋₈), or alkynyl (C₃₋₈), straight chain or branched, and maybe substituted with one or more of halogen, hydroxyl, alkoxy(C₁₋₄),alkyl(C₁₋₄)sulfone, or alkoxycarbonyl(C₁₋₅), provided that R₃ and R₄cannot both be hydrogen; or R₃ and R₄ together with the nitrogen atommay be incorporated into a saturated heterocyclic ring selected from:##STR9## p is 1-4; L₁ and L₂ are independently chosen from --(CH₂)q--,wherein q is 2 or 3, or --CHR₇ CH₂ --; Q is O, NR₆, S or SO₂ ; R₅ ishydrogen, alkyl (C₁₋₄), alkoxy (C₁₋₃), alkoxy(C₁₋₃)alkyl(C₂₋₄),alkoxycarbonyl(C₁₋₅) or hydroxyalkyl (C₁₋₃); R₆ is hydrogen,hydroxyalkyl (C₂₋₄), alkoxy(C₁₋₃)alkyl(C₂₋₄), alkyl(C₂₋₄)carbonyl oralkyl(C₁₋₃)sulfonyl; and R₇ is alkyl (C₁₋₄), alkoxy (C₁₋₃),alkoxycarbonyl(C₁₋₅) or hydroxyalkyl (C₁₋₃); provided that R₁ is NR₃ R₄when G is alkyl(C₁₋₄) or hydrogen, and R₁ can not be NR₃ R₄ when G isnot alkyl(C₁₋₄) or hydrogen; or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable vehicle therefor.
 2. A methodaccording to claim 1, wherein G is NR₃ R₄.
 3. A method according toclaim 1, wherein X is O.
 4. A method according to claim 1, wherein X isSO_(m).
 5. A method according to claim 1, wherein the compound isselected from the group consistingof:1-[2,3-Dichloro-4-[2-(4-morpholinyl)ethoxy]phenyl]-2-methylene-1-butanone;1-[2,3-Dichloro-4-[2-(4-morpholinyl)ethoxy]phenyl]-2-methylene-1-propanone;1-[3-Chloro-4-[2-(4-morpholinyl)ethoxy]phenyl]-2-methylene-1-butanone;1-[2,3-Dichloro-4-[2-[bis(2-methoxyethyl)amino]ethoxy]phenyl]-2-methylene-1-butanone;1-[3-Chloro-4-[2-[bis(2-methoxyethyl)amino]ethoxy]phenyl]-2-methylene-1-butanone;1-[2,3-Dichloro-4-[3-methoxy-2-[(2-methoxyethyl)methylamino]propoxy]phenyl]-2-methylene-1-butanone;1-[2,3-Dichloro-4-[(4-methyl-3-morpholinyl)methoxy]phenyl]-2-methylene-1-butanone;1-[3-Chloro-4-[(4-methyl-3-morpholinyl)methoxy]phenyl]-2-methylene-1-butanone;1-[3-Chloro-4-[(2-(2-fluoroethyl)methylamino)ethoxy]phenyl]-2-methylene-1-butanone;1-[3-Chloro-4-[(4-(2-methoxyethyl)-3-morpholinyl)methoxy]phenyl]-2-methylene-1-butanone;1-[4-[2-(4-Morpholinyl)ethoxy]phenyl]-2-methylene-1-butanone;1-[4-[3-methoxy-2-[(2-methoxyethyl)methylamino]propoxy]phenyl]-2-methylene-1butanone;1-[3-Chloro-4-[2-[(1-propyn-3-yl)methylamino]ethoxy]phenyl]-2-methylene-1butanone;and1-[4-[(4-(2-Hydroxyethyl)-3-morpholiny)methoxy]phenyl]-2-methylene-1-butanone.